Liquid polymer delivery system for extended administration of drugs

ABSTRACT

Liquid polymer pharmaceutical compositions with a biodegradable liquid polyester that has a carboxylic acid end group, a biocompatible solvent, and an active pharmaceutical agent are useful for administration into the body to provide extended long term release of the drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/749,030, filed 30 Jan. 2018, which is a national stage applicationunder 35 U.S.C. 371 of PCT Application No. PCT/US2016/045334, having aninternational filing date of 3 Aug. 2016, which designated the UnitedStates, which PCT claimed the benefit of U.S. Provisional PatentApplication 62/200,198, filed 3 Aug. 2015, and U.S. Provisional PatentApplication 62/275,407, filed 6 Jan. 2016, the entireties of these whichare incorporated herein by reference.

FIELD OF THE INVENTION

This application pertains to the field of biodegradable liquid polymercompositions that may be administered into the body with syringes orneedles and that may be utilized to deliver a drug into the body over anextended period of time.

BACKGROUND OF THE INVENTION

Biodegradable polymers are well known for their use in biomedicalapplications, such as sutures, surgical clips, staples, implants, anddrug delivery systems. Such polymers include polyglycolides,polylactides, polycaprolactones, polyanhydrides, polyorthoesters,polydioxanones, polyacetals, polyesteramides, polyamides, polyurethanes,polycarbonates, poly(amino acids), polyphosphazenes, polyketals,polyhydroxybutyrates, polyhydroxyalerates, and polyalkylene oxalates.

Initially, the biodegradable polymers were solid materials that wereused to form solid articles such as sutures, staples, surgical clips,implants or microcapsules and microparticles. Because the polymers weresolids, all of their applications in the biomedical field required thatthe polymeric structures be formed outside the body, and then insertedinto the body for their use.

U.S. Pat. No. 5,278,201 to Dunn et al. (the “'201 patent”) overcame theadministration problems with the solid implants by dissolving the solidbiodegradable polymers in a biocompatible solvent and injecting thesolution into the body using standard syringes and needles where thepolymer in the solution precipitates or coagulates upon contact withaqueous body fluid to form a solid implant matrix. The delivery systemdescribed in the '201 patent offered a number of advantages, includingthe ease of manufacture of the polymer solution, the incorporation ofthe drug into the polymer solution just prior to administration leadingto increased drug and polymer stability as well as no loss of drugduring the manufacturing process, and the ability to terminallysterilize the polymer solution as well as the drug. However, thereremained several disadvantages with this in situ forming polymer system.Because the polymers used were solids with relatively high molecularweights, the polymer solutions formed from the combination of the solidpolymers and the biocompatible solvents were quite viscous. Because ofthe high viscosity, large bore 18-21 gauge needles were required foradministration and considerable injection force was needed. In addition,the viscous solutions were not easily injected into muscle tissue andthe solid implants formed from these polymer solutions tend to causelocal irritation of the muscular tissue. For this reason, the foregoingpolymer solutions were normally injected subcutaneously where thematerial would form quite distinct and noticeable bumps.

U.S. Pat. No. 8,187,640 to Dunn (the “'640 patent”) addressed and solvedproblems associated with the solid implants of the '201 patent. The '640patent disclosed solution compositions of a biodegradable liquid polymercombined with a biocompatible organic solvent, which solvent woulddissipate when the liquid polymer/solvent compositions were placed in abody, thereby forming a viscous liquid polymer material in the form of afilm, a coating, a plug or other mass. The viscous liquid polymermaterial does not solidify upon injection into the body, but ratherremains in situ in a viscous liquid form and, when combined with a drug,provides both an initial burst and extended release of the drug.

The '640 patent further disclosed that the rate of release of a drugfrom the in situ viscous liquid material can be controlled by alteringthe composition of the biodegradable polymer. The composition of theliquid polymer, i.e., the type of monomer used or the ratio of monomersfor copolymers or terpolymers, the end groups on the polymer chains, andthe molecular weight of the polymer, determines the hydrophilicity orlipophilicity of the polymer material, as well as the degradation timeof the liquid polymer implant. For faster release rates and shorterdurations of release, such as over a period of 1 to 3 days, morehydrophilic polymers can be used. On the other hand, for slower releaseof drug and longer duration of release, such as over a period of 7 to 90days, more hydrophobic polymer can be used.

The '640 patent does not disclose examples of suitable variations of theend groups of the polymer chains. However, in the Examples section, thispatent discloses the use of an alcohol, dodecanol, as an initiator,which results in the insertion of an hydroxy group at the end of thepolymer chain.

As described in more detail below, the inventors of the presentapplication have made the low viscosity liquid polymeric delivery systemas disclosed in the '640 patent to determine the rate and duration ofrelease of drugs following subcutaneous administration of thedrug-loaded delivery system. It was determined that the drug wasreleased in a burst during the initial 24 hours followingadministration, which was followed by slower release that persisted for14 days. After 14 days, no significant quantity of drug was released. Itwas therefore determined that the delivery system of the '640 patent isnot suitable for long-term extended delivery of drugs.

SUMMARY OF THE INVENTION

It is one aspect of the present invention to provide a liquid polymercomposition for administration into the body of an animal. The liquidpolymer composition has a biodegradable liquid polyester with at leastone carboxylic acid end group, and a biocompatible organic solvent. Aratio of monomer units to carboxylic acid end groups in thebiodegradable liquid polyester is between about 5:1 and about 90:1.

In some embodiments, the biodegradable liquid polyester may be selectedfrom the group consisting of a polylactide, a polyglycolide, apolycaprolactone, a poly(trimethylene carbonate), a polydioxanone, acopolymer thereof, a terpolymer thereof, or any combination thereof.

In some embodiments, the carboxylic acid may be selected from the groupconsisting of GABA (gamma-amino butyric acid), GHB (gamma-hydroxybutyricacid), lactic acid, glycolic acid, citric acid, and undecylenic acid.

In some embodiments, the biodegradable liquid polyester may have atleast about 50% lactide residues.

In some embodiments, the biodegradable liquid polyester may have about75% lactide residues.

In some embodiments, the biodegradable liquid polyester may have monomerresidues selected from the group consisting of caprolactone,trimethylene carbonate and combinations thereof in an amount less thanabout 50%.

In some embodiments, the biodegradable liquid polyester may have about25% monomer residues selected from the group consisting of caprolactone,trimethylene carbonate and combinations thereof.

In some embodiments, the biodegradable liquid polyester may be selectedfrom the group consisting of 75:25 lactide:caprolactone and 75:25lactide:trimethylene carbonate.

In some embodiments, the biodegradable liquid polyester may have anaverage molecular weight between about 15 kDa and about 30 kDa.

In some embodiments, the biocompatible organic solvent may be at leastpartially made up of one or more organic solvents selected from thegroup consisting of amides, acids, alcohols, esters of monobasic acids,ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters ofpolyhydroxy alcohols, ketones, and ethers.

In some embodiments, the biocompatible organic solvent may be at leastpartially made up of one or more organic solvents selected from thegroup consisting of N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone,N-ethyl-2-pyrrolidone, N-cycylohexyl-2-pyrrolidone,N-hydroxyethyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide,acetic acid, lactic acid, ethanol, propanol, methyl lactate, ethyllactate, methyl acetate, diethylene glycol monomethyl ether, glycofurol,glycerol formal, isopropylidene glycerol, dimethyl sulfoxide,e-caprolactone, butyrolactone, propylene glycol, polyethylene glycol,glycerol, 1,3-butyleneglycol, methoxypolyethylene glycol,methoxypropylene glycol, acetone, methyl ethyl ketone, andtetrahydrofuran.

In some embodiments, the composition may be between about 20 wt % andabout 40 wt % biodegradable liquid polyester and between about 40 wt %and about 60 wt % biocompatible organic solvent.

In some embodiments, the animal may be a human.

It is another aspect of the invention to provide a liquid polymerpharmaceutical composition for administration into the body of ananimal. The liquid polymer pharmaceutical composition has abiodegradable liquid polyester with at least one carboxylic acid endgroup, a biocompatible organic solvent, and an active pharmaceuticalagent. A ratio of monomer units to carboxylic acid end groups in thebiodegradable liquid polyester is between about 5:1 and about 90:1.

In some embodiments, the active pharmaceutical agent may be present in adosage effective for greater than three days.

In some embodiments, the active pharmaceutical agent may be present in adosage effective for greater than one week.

In some embodiments, the active pharmaceutical agent may be present in adosage effective for greater than one month.

In some embodiments, the active pharmaceutical agent may be present inan amount between 0.1% and 60% by weight of the composition.

In some embodiments, the drug may be a hydrophobic small molecule drug.The hydrophobic small molecule drug may be selected from the groupconsisting of corticosteroids, azole medications, sex steroids, statindrugs, and antiandrogen drugs. The hydrophobic small molecule drug mayalso be selected from the group consisting of testosterone, prednisone,triamcinolone, prednisolone, beclomethasone, fluticasone,methylprednisone, clobetasol, halobetasol, dexamethasone, metronidazole,fluconazole, ketoconazole, itraconazole, miconazole, dimetridazole,secnidazole, ornidazole, tinidazole, carnidazole, panidazole, estrogens,progestins, including esters thereof, atorvastatin, simvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin,abiraterone, galeterone, orteronel, enzalutamide, and salts, esters,complexes, prodrugs, and analogs thereof.

In some embodiments, the drug may be a polymeric drug. The polymericdrug may be selected from the group consisting of degarelix,abaloparatide, leuprolide (leuprorelin), exenatide, liraglutide,albiglutide, dulaglutide, basal insulin, octreotide, goserelin,triptorelin, nafarelin, buserelin, histrelin, deslorelin, ganirelix,abarelix, cetrorelix, teverelix, lanreotide, carfilzomib, human growthhormone, interferon-alpha, interferon-beta, interferon-gamma,interleukin, calcitonin, growth hormone releasing peptides,glucagon-like peptides, granulocyte-colony stimulating factor, nervegrowth factor, platelet-derived growth factor, insulin-like growthfactor, vascular endothelial growth factor, fibroblast growth factor,bone morphogenic protein, erythropoietin, poly-L-lactic acid (PLLA), andsalts, esters, complexes, prodrugs, and analogs thereof. The polymericdrug may also be selected from the group consisting of degarelix,abaloparatide, leuprolide (leuprorelin), exenatide, liraglutide,albiglutide, dulaglutide, basal insulin, octreotide, goserelin,triptorelin, nafarelin, buserelin, histrelin, deslorelin, ganirelix,abarelix, cetrorelix, teverelix, lanreotide, carfilzomib, and salts,esters, complexes, prodrugs, and analogs thereof.

In some embodiments, the biodegradable liquid polyester may be selectedfrom the group consisting of a polylactide, a polyglycolide, apolycaprolactone, a poly(trimethylene carbonate), a copolymer thereof, aterpolymer thereof, or any combination thereof.

In some embodiments, the carboxylic acid may be selected from the groupconsisting of GABA (gamma-amino butyric acid), GHB (gamma-hydroxybutyricacid), lactic acid, glycolic acid, citric acid, and undecylenic acid.

In some embodiments, the biodegradable liquid polyester may have atleast about 50% lactide residues.

In some embodiments, the biodegradable liquid polyester may have about75% lactide residues.

In some embodiments, the biodegradable liquid polyester may have monomerresidues selected from the group consisting of caprolactone,trimethylene carbonate and combinations thereof in an amount less thanabout 50%.

In some embodiments, the biodegradable liquid polyester may have about25% monomer residues selected from the group consisting of caprolactone,trimethylene carbonate and combinations thereof.

In some embodiments, the biodegradable liquid polyester may be selectedfrom the group consisting of 75:25 lactide:caprolactone and 75:25lactide:trimethylene carbonate.

In some embodiments, the biodegradable liquid polyester may have anaverage molecular weight between about 15 kDa and about 30 kDa.

In some embodiments, the biocompatible organic solvent may be at leastpartially made up of one or more biocompatible organic solvents thathave a water solubility of 10% or higher by weight of the solvent inwater.

In some embodiments, the biocompatible organic solvent may be at leastpartially made up of one or more organic solvents selected from thegroup consisting of amides, acids, alcohols, esters of monobasic acids,ether alcohols, sulfoxides, lactones, polyhydroxy alcohols, esters ofpolyhydroxy alcohols, ketones, and ethers.

In some embodiments the biocompatible organic solvent may be at leastpartially made up of one or more organic solvents selected from thegroup consisting of N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone,N-ethyl-2-pyrrolidone, N-cycylohexyl-2-pyrrolidone,N-hydroxyethyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide,acetic acid, lactic acid, ethanol, propanol, methyl lactate, ethyllactate, methyl acetate, diethylene glycol monomethyl ether, glycofurol,glycerol formal, isopropylidene glycerol, dimethyl sulfoxide,e-caprolactone, butyrolactone, propylene glycol, polyethylene glycol,glycerol, 1,3-butyleneglycol, methoxypolyethylene glycol,methoxypropylene glycol, acetone, methyl ethyl ketone, andtetrahydrofuran.

In some embodiments, the composition may be between about 20 wt % andabout 40 wt % biodegradable liquid polyester, between about 40 wt % andabout 60 wt % biocompatible organic solvent, and between about 10 wt %and about 30 wt % active pharmaceutical agent.

In some embodiments, the animal may be a human.

It is another aspect of the invention to provide a method of forming abiodegradable, non-solid implant in situ in a body. The method includesthe step of injecting a liquid polymer composition into the body. Theliquid polymer composition has a biodegradable liquid polyester with atleast one carboxylic acid end group, and a biocompatible organicsolvent. A ratio of monomer units to carboxylic acid end groups in thebiodegradable liquid polyester is between about 5:1 and about 90:1.

It is another aspect of the invention to provide a method of deliveringan active pharmaceutical agent to a body. The method includes the stepof injecting a liquid polymer pharmaceutical composition into the body.The liquid polymer composition has a biodegradable liquid polyester withat least one carboxylic acid end group, a biocompatible organic solvent,and an active pharmaceutical agent. A ratio of monomer units tocarboxylic acid end groups in the biodegradable liquid polyester isbetween about 5:1 and about 90:1. The active pharmaceutical agent isreleased within the body for at least three days.

It is another aspect of the invention to provide a liquid polymerpharmaceutical composition for administration into the body of ananimal. The liquid polymer pharmaceutical composition has abiodegradable liquid polyester, a biocompatible organic solvent, and anactive pharmaceutical agent. The polyester is apoly(DL-lactide-co-caprolactone) with a carboxylic acid end group. Theactive pharmaceutical agent is selected from the group consisting oftestosterone, degarelix, abaloparatide, leuprolide, and pharmaceuticallyacceptable salts and esters thereof.

In some embodiments, the biodegradable liquid polyester may have atleast about 50% lactide residues.

In some embodiments, the biodegradable liquid polyester may have lessthan about 50% caprolactone residues.

In some embodiments, the biodegradable liquid polyester may be 75:25lactide:caprolactone.

In some embodiments, the biodegradable liquid polyester may have anaverage molecular weight between about 15 kDa and about 30 kDa.

In some embodiments, the biodegradable liquid polyester may have anaverage molecular weight between about 20 kDa and about 25 kDa.

In some embodiments, the biocompatible organic solvent may be at leastpartially made up of N-methyl-2-pyrrolidone.

In some embodiments, the active pharmaceutical agent may be testosteroneundecanoate.

In some embodiments, the active pharmaceutical agent may be selectedfrom the group consisting of degarelix and degarelix acetate.

In some embodiments, the active pharmaceutical agent may beabaloparatide.

In some embodiments, the active pharmaceutical agent may be leuprolideacetate.

In some embodiments, the composition may be between about 20 wt % andabout 40 wt % biodegradable liquid polyester, between about 40 wt % andabout 60 wt % biocompatible organic solvent, and between about 10 wt %and about 30 wt % active pharmaceutical agent.

In some embodiments, the animal may be a human.

It is another aspect of the invention to provide a delivery system foradministration of a liquid polymer pharmaceutical composition. Thedelivery system has a syringe component, a formulation component with abiodegradable liquid polyester having at least one carboxylic acid endgroup, and an active pharmaceutical agent. A ratio of monomer units tocarboxylic acid end groups in the biodegradable liquid polyester isbetween about 5:1 and about 90:1. The formulation component and theactive pharmaceutical agent are contained within the syringe component.

In some embodiments, the syringe component may be a single syringecontaining the formulation component and the active pharmaceuticalagent.

In some embodiments, the syringe component may be a two syringe system,with a first syringe containing the formulation component and a secondsyringe containing the active pharmaceutical agent.

It is another aspect of the invention to provide a liquid polymercomposition for administration into the body of an animal or human. Theliquid polymer composition has a biodegradable liquid polymer with acarboxylic acid end group, a biocompatible organic solvent, and atherapeutically effective amount of a drug.

It is another aspect of the invention to provide a liquid polymerpharmaceutical composition. The liquid polymer pharmaceuticalcomposition has a biodegradable liquid polyester with at least onecarboxylic acid end group, a biocompatible organic solvent, and anactive pharmaceutical agent selected from the group consisting oftestosterone and pharmaceutically acceptable salts and esters thereoffor use in the treatment of androgen deficiency. A ratio of monomerunits to carboxylic acid end groups is between about 5:1 and about 90:1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing blood levels of testosterone (ng/ml) over timein rats injected subcutaneously with a prior art liquid polymer deliverysystem containing a 50% DL-lactide and 50% ε-caprolactone initiated withdodecanol and a solvent (N-methyl-2-pyrrolidone (NMP)), combined withtestosterone. Symbols: Control composition of the liquid polymerdelivery system and lacking testosterone (♦), Test Composition 1 made of35% the prior art liquid polymer, 25% the solvent, and 40% testosterone(▪), Test Composition 2 made of 40% the prior art liquid polymer, 40%the solvent, and 20% testosterone (▴), Test Composition 3 made of 35%the prior art liquid polymer, 25% the solvent, and 40% testosterone (x),Test Composition 4 made of 40% the prior art liquid polymer, 40% thesolvent, and 20% testosterone (-), and Test Composition 5 made of 40% ofa prior art liquid polymer (75% DL-lactide and 25% ε-caprolactone), 20%the solvent, and 40% testosterone (●).

FIG. 2 is a graph showing blood levels of testosterone (ng/ml) over timein rats injected subcutaneously with one of three test compositionscontaining testosterone, a glycolic acid initiated liquid polymercontaining 75% DL-lactide and 25% ε-caprolactone, and a solvent.Symbols: Test Composition A made of 30% the liquid polymer having amolecular weight of 8 kDa, 30% the solvent NMP, and 40% testosterone(▪), Test Composition B made of 30% liquid polymer having a molecularweight of 22 kDa, 30% the solvent NMP, and 40% testosterone (♦), TestComposition C made of 30% liquid polymer having a molecular weight of 15kDa, 30% the solvent combination of 30% NMP and 70% benzyl benzoate, and40% testosterone (▴).

FIG. 3 is a graph showing blood levels of testosterone (ng/ml) over timein rats injected subcutaneously with one of three test compositionscontaining an ester of testosterone (testosterone cypionate), a glycolicacid initiated liquid polymer containing 75% DL-lactide and 25%ε-caprolactone, and a solvent. Symbols: Test Composition D made of 30%of a liquid polymer having a molecular weight of 22 kDa, 50% the solventNMP, and 20% testosterone cypionate (▪), Test Composition E made of 30%of a liquid polymer having a molecular weight of 25 kDa, 45% the solventNMP, and 25% testosterone cypionate (♦), Test Composition F made of 30%of a liquid polymer having a molecular weight of 25 kDa, 50% the solventNMP, and 20% testosterone cypionate (▴).

FIG. 4 is a graph showing blood levels of testosterone (ng/ml) over timein rats injected subcutaneously with one of four test compositionscontaining an ester of testosterone (testosterone undecanoate), aglycolic acid initiated liquid polymer containing 75% DL-lactide and 25%ε-caprolactone, and a solvent. Symbols: Test Composition G made of 20%of a liquid polymer having a molecular weight of 8 kDa, 60% the solventNMP, and 20% testosterone undecanoate (▪), Test Composition H made of30% of a liquid polymer having a molecular weight of 8 kDa, 50% thesolvent NMP, and 20% testosterone undecanoate (♦), Test Composition Imade of 20% of a liquid polymer having a molecular weight of 22 kDa, 60%the solvent NMP, and 20% testosterone undecanoate (▴), and TestComposition J made of 30% of a liquid polymer having a molecular weightof 22 kDa, 50% the solvent NMP, and 20% testosterone undecanoate (●).

FIG. 5 is a graph comparing release of polymeric drug from a liquidpolymer composition in which the liquid polymer is initiated withdodecanol (♦) and from a liquid polymer composition in which the sameliquid polymer is initiated with glycolic acid (▪).

FIG. 6 is a graph showing release of polymeric drug from liquid polymercompositions in which the liquid polymer is initiated with glycolicacid. Symbols: Composition K contained 30% of a liquid polymer having amolecular weight of 14 kDa, 58% the solvent NMP, and 12% leuprolideacetate (♦); Composition L contained 35% of a liquid polymer having amolecular weight of 14 kDa, 53% the solvent NMP, and 12% leuprolideacetate (▪); and Composition M contained 40% of a liquid polymer havinga molecular weight of 14 kDa, 48% the solvent NMP, and 12% leuprolideacetate (▴).

FIG. 7 is a graph showing release of polymeric drug from liquid polymercompositions in which the liquid polymer is initiated with glycolicacid. Composition N contained 30% of a liquid polymer having a molecularweight of 8 kDa, 58% the solvent NMP, and 12% leuprolide acetate (▪);Composition O contained 35% of a liquid polymer having a molecularweight of 8 kDa, 53% the solvent NMP, and 12% leuprolide acetate (▴);and Composition P contained 40% of a liquid polymer having a molecularweight of 8 kDa, 48% the solvent NMP, and 12% leuprolide acetate (●).

FIGS. 8A and 8B are graphs showing non-normalized and normalized (fordose and body weight) pK data, respectively, showing the release oftestosterone over time in rats injected subcutaneously with CompositionsQ (▪) and R (♦) and a control formulation (▴). Composition Q (▪)contained 20% testosterone undecanoate, 30% lactic acid-initiated liquidpolymer containing 75% DL-lactide and 25% ε-caprolactone and having amolecular weight of 22 kDa, and 50% NMP. Composition R (♦) contained 20%testosterone undecanoate, 30% glycolic acid-initiated liquid polymercontaining 75% DL-lactide and 25% trimethylene carbonate and having amolecular weight of 22 kDa, and 50% NMP. A control formulation (▴)contained 20% testosterone undecanoate, 30% glycolic acid-initiatedliquid polymer containing 75% DL-lactide and 25% ε-caprolactone andhaving a molecular weight of 22 kDa, and 50% NMP.

DETAILED DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that, in a liquid polymer deliverysystem that includes a biodegradable liquid polymer combined with abiocompatible organic solvent, such as disclosed in U.S. Pat. No.8,187,640, the disclosure of which is incorporated herein in itsentirety, utilizing a polymer having carboxylic acid end groups asdescribed herein surprisingly provides markedly improved extendedrelease of drugs.

This discovery was especially surprising in view of the fact that the'640 patent discloses that faster release rates and shorter durations ofrelease are obtained with increased hydrophilicity of the liquidpolymer. In contrast to what would be expected by a skilled artisan,utilizing a carboxylic acid end group, which is highly hydrophilic,provides a markedly longer duration of release of drugs.

As used herein, the term “animal” refers to any organism of the kingdomAnimalia. Examples of “animals” as that term is used herein include, butare not limited to, humans (Homo sapiens); companion animals, such asdogs, cats, and horses; and livestock animals, such as cows, goats,sheep, and pigs.

As used herein, the term “biocompatible” means “not harmful to livingtissue.”

As used herein, the term “biodegradable” refers to any water-insolublematerial that is converted under physiological conditions into one ormore water-soluble materials, without regard to any specific degradationmechanism or process.

As used herein, the term “liquid” refers to the ability of a compositionto undergo continuous deformation under a shearing stress. Liquidpolymer compositions and the liquid polymers according to the inventionhave a liquid physical state at ambient and body temperatures. Theliquid polymer compositions and liquid polymers have a definite volume,but are an amorphous, non-crystalline mass with no definite shape. Inaddition, the liquid polymers according to the invention are not solublein body fluid or water and therefore, after injection into the body anddissipation of the solvent, remain as a cohesive mass when injected intothe body without themselves significantly dissipating. In addition, suchliquid polymer compositions can have a viscosity, density, andflowability to allow delivery of the composition through standard gaugeor small gauge needles (e.g., 18-26 gauge) with low to moderateinjection force using standard syringes. The liquid polymers of thepresent invention can be further characterized as not forming a solidimplant in situ in the body when injected into the body as part of asustained release drug delivery system that includes the liquid polymersand a biocompatible solvent. The liquid polymers of the presentinvention can be further characterized being non-crystalline, amorphous,non-thermoplastic, non-thermosetting, and/or non-solid.

As used herein, the terms “molecular weight” and “average molecularweight,” unless otherwise specified, mean a weight-average molecularweight as measured by a conventional gel permeation chromatography (GPC)instrument (such as an Agilent 1260 Infinity Quaternary LC with AgilentG1362A Refractive Index Detector) utilizing polystyrene standards andtetrahydrofuran (THF) as the solvent.

As used herein, the terms “patient” and “subject” are interchangeableand refer generally to an animal to which a composition or formulationof the invention is administered or is to be administered.

As used herein, the term “polymer” refers generally to polymers,copolymers and/or terpolymers that can be linear, branched, graftedand/or star-shaped. Examples of polymers include peptides, polypeptides,proteins, and nucleic acids.

As used herein, the term “small molecule” means an organic compoundhaving a molecular weight less than 900 daltons.

Unless otherwise specified, all ratios between monomers in a copolymerdisclosed herein are molar ratios.

The liquid polymer compositions of the invention comprise abiodegradable liquid polyester and a biocompatible organic solvent andare prepared by mixing or blending together the liquid polymer(s) andthe organic solvent(s), which can be performed by any method at atemperature ranging from about 10-50° C. (e.g., at about 25° C.) using asuitable device to achieve a homogeneous, flowable liquid at roomtemperature. Examples of such devices include a mechanical stirrer, amixer, or a roller mill. Because both the polymer and solvents areliquids, they are readily mixed to form a homogeneous solution orsuspension.

Polymers with a carboxylic acid end group, such as a glycolic acid endgroup, may be made by standard chain-growth polymerization techniques,by combining one or more alkene or alicyclic monomers with a carboxylicacid or water, preferably a hydroxy acid, in the presence of a suitablecatalyst, such as tin, for example in the form of stannous octanoate.Carboxylic acids that are suitable are those that contain an alkylchain, a nucleophile, and are soluble in the monomer used to make thepolymer or a combination of the monomer and solvent. Examples ofsuitable initiators include, but are not limited to, GABA (gamma-aminobutyric acid), GHB (gamma-hydroxybutyric acid), lactic acid, glycolicacid, citric acid, and water. Typically, a biodegradable polymer with anacid end group is made by the ring opening polymerization of monomers,such as lactide and/or caprolactone, which is initiated by water or acarboxylic acid compound of the formula Nu-R—COOH where Nu is anucleophilic moiety, such as an amine or hydroxyl, R is any organicmoiety, and the —COOH is a carboxylic acid functionality. Thenucleophilic moiety of the molecule acts to initiate the ring openingpolymerization in the presence of a catalyst and heat, producing apolymer with a carboxylic acid functionality on one end. Arepresentative polymerization equation is shown below as Formula A.

Alternatively, a carboxylic acid end group may be created on the end ofa polymer chain by post-polymerization modification.

The liquid polymers that can be used according to the present inventionare biodegradable, and remain in a liquid (flowable) form at roomtemperature (e.g., at approximately 25° C.) up to body temperature(e.g., at approximately 37° C.). The characteristic of being liquid isachieved by control of the molecular weight of the polymer and themonomer selection and ratio. In addition, the liquid polymer can have apre-injection bulk viscosity that allows the composition to be easilyadministered, and in some embodiments effective to provide a desiredcontrolled release profile of a biologically active agent from theimplanted material. Because the liquid polymers are liquid at roomtemperature, they allow the use of lower concentrations of thebiocompatible solvent to be used in the composition to provide asyringeable formulation compared to polymer/solvent compositionsprepared with solid polymers.

Examples of suitable liquid polymers that can be used in thisapplication include polylactic acid, polyglycolic acid, polylactide(DL-lactide, D-lactide, L-lactide), polyglycolide, polycaprolactones,polyanhydrides, polyamides, polyurethanes, polyesteramides,polyorthoesters, polydioxanones, polyacetals, polyketals,polycarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), polyethylene glycol, hyaluronic acid, chitin andchitosan, and copolymers, terpolymers, and combinations or mixtures ofthe above materials. In one embodiment, the liquid polymer is selectedfrom the group consisting of a polylactide, a polyglycolide, apolycaprolactone, a poly(trimethylene carbonate), a polydioxanone, acopolymer thereof, a terpolymer thereof, or any combination thereof.Preferred materials include those polymers, copolymers or terpolymersmade with lactide, glycolide, caprolactone, p-dioxanone, trimethylenecarbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide,propylene oxide, sebacic anhydride, diketene acetals/diols, and lacticacid with lower molecular weights and amorphous regions to limitcrystallinity and subsequent solidification.

Non-limiting examples of suitable liquid polymers according to theinvention include copolymers of DL-lactide and ε-caprolactone with molarratios of lactide/caprolactone ranging from about 75/25 to about 50/50and optionally with inherent viscosities as determined in a 0.10 g/dLsolution of hexafluoroisopropanol (HFIP) at 25° C. from about 0.06 toabout 0.38 dL/g, copolymers of caprolactone and 1,4-dioxanone with molarratios of about 70/30 to about 40/60 and optionally with inherentviscosities of about 0.08 to about 0.24 dL/g, lactide and trimethylenecarbonate copolymers such as 75/25 poly(DL-lactide-co-trimethylenecarbonate), copolymers of caprolactone and trimethylene carbonate withmolar ratios of about 90/10 to about 50/50 and optionally with inherentviscosities of about 0.09 to about 0.25 dL/g, and poly(L-lactic acid)optionally with an inherent viscosity of about 0.06 dL/g, among others.Generally, liquid polymers and liquid polymer compositions of theinvention can have an inherent viscosity as determined in a 0.10 g/dLsolution of hexafluoroisopropanol at 25° C. from 0.05 to 0.50 dL/g.

In embodiments of the composition, the biodegradable liquid polymer is acopolymer of two monomers having a molar ratio of about 75/25 to about25/75 with a preferred ratio of about 50/50, and an average molecularweight of between about 5,000 daltons and about 40,000 daltons,preferably between about 15,000 daltons and about 30,000 daltons, andmore preferably between about 20,000 and about 25,000 daltons. Themolecular weight of the biodegradable liquid polymer may be about 8,000daltons, about 14,000 daltons, about 15,000 daltons, about 22,000daltons, or about 25,000 daltons, as exemplified in the Examples below.

Further examples of suitable liquid polymers of the invention includebiodegradable liquid polyesters with at least about 50% lactide(including DL-lactide) residues, at least about 55% lactide residues, atleast about 60% lactide residues, at least about 65% lactide residues,at least about 70% lactide residues, or at least about 75% lactideresidues. Other examples of suitable liquid polymers of the inventioninclude biodegradable liquid polyesters with residues of comonomersselected from caprolactone, trimethylene carbonate and combinationsthereof in an amount greater than about 5% and less than about 50%, lessthan about 45% such residues, less than about 40% such residues, lessthan about 35% such residues, less than about 30% such residues, or lessthan about 25% such residues. Further embodiments include liquidpolyesters of about 75:25 DL-lactide:ε-caprolactone and of 75:25DL-lactide:trimethylene carbonate.

The biodegradable liquid polyesters of the invention are alsocharacterized as having at least one carboxylic acid end group. Further,the polyesters can have a ratio of monomer units to carboxylic acid endgroups that is between about 5:1 and about 90:1, between about 10:1 andabout 90:1, between about 15:1 and about 90:1, between about 20:1 andabout 90:1, between about 30:1 and about 80:1, between about 40:1 andabout 70:1, between about 50:1 and about 60:1, or about 55:1.Alternatively, the ratio of monomer units to carboxylic acid end groupscan be less than about 90:1, less than about 80:1, less than about 70:1,less than about 60:1, or less than about 55:1. The ratio of monomerunits to carboxylic acid end groups can range from any whole numberratio to any other whole number ratio within the range of about 5:1 toabout 90:1.

The liquid polymers of the invention have a molecular weight suitablefor achieving the characteristic of being liquid. In particular, themolecular weight of the polymers can be from about 5,000 daltons toabout 40,000 daltons, from about 10,000 daltons to about 35,000 daltons,from about 8,000 daltons to about 25,000 daltons, from about 15,000daltons to about 30,000 daltons, or from about 20,000 to about 25,000daltons. The molecular weight of the polymers can also be between about5,000 daltons and about 11,000 daltons, between about 6,000 daltons andabout 10,000 daltons, between about 7,000 daltons and about 9,000daltons, or about 8,000 daltons. The molecular weight of thebiodegradable liquid polymer may be about 8,000 daltons, about 14,000daltons, about 15,000 daltons, about 22,000 daltons, or about 25,000daltons, as exemplified in the Examples below. The molecular weight ofthe polymer can range from any number of daltons to any other number ofdaltons within the range of about 5,000 daltons to about 40,000 daltons.In addition, the liquid polymers of the invention can have apolydispersity value of from about 1.30 to about 2.50, from about 1.35to about 2.25, or from about 1.40 to about 2.00.

Solvents that may be used according to the invention are non-toxic andcan be either hydrophilic or hydrophobic solvents, or may be acombination of hydrophilic solvents, hydrophobic solvents or hydrophilicand hydrophobic solvents, depending upon the desired release profile andthe solubility of the polymer and/or biologically active agent in thepolymer/solvent composition. Suitable hydrophilic biocompatible organicsolvents that can be used according to the present invention have awater solubility of 10% or higher by weight of the solvent in water.Examples of hydrophilic biocompatible organic solvents include amidessuch as N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone,N-ethyl-2-pyrrolidone, N-cycylohexyl-2-pyrrolidone,N-hydroxyethyl-2-pyrrolidone, dimethyl acetamide, and dimethylformamide; acids such as acetic acid and lactic acid; alcohols such asethanol and propanol; esters of monobasic acids such as methyl lactate,ethyl lactate, and methyl acetate; ether alcohols such as diethyleneglycol monomethyl ether, glycofurol, glycerol formal, and isopropylideneglycerol (Solketal); sulfoxides such as dimethyl sulfoxide; lactonessuch as ε-caprolactone and butyrolactone; polyhydroxy alcohols such aspropylene glycol, polyethylene glycol, glycerol, and 1,3-butyleneglycol;esters of polyhydroxy alcohols such as methoxypolyethylene glycol andmethoxypropylene glycol; ketones such as acetone and methyl ethylketone; and ethers such as tetrahydrofuran.

Suitable hydrophobic biocompatible organic solvents that can be usedaccording to the invention have a water solubility less than 10% byweight of the solvent in water. Examples of hydrophobic biocompatibleorganic solvents include esters of mono-, di-, and tricarboxylic acidssuch as ethyl acetate, ethyl butyrate, ethyl oleate, isopropylpalmitate, ethyl palmitate, methyl palmitate, isopropyl myristate,diethyl malonate, diethyl succinate, dimethyl adipate, dimethylsuccinate, dibutyl sebacate, triacetin, triethyl citrate, tributyrin,acetyl triethyl citrate, acetyl tributyl citrate, acetyl trihexylcitrate, butyryl trihexyl citrate, and tributyl citrate; esters ofcaprylic and/or capric acids with glycerol or alkylene glycols such asMIGLYOL 810 or 812 (SASOL GERMANY GMBH) (caprylic/capric triglycerides),MIGLYOL 818 (caprylic/capric/linoleic triglyceride), MIGLYOL 829(caprylic/capric/succinic triglyceride), and MIGLYOL 840 (propyleneglycol dicaprylate/caprate); aromatic alcohols such as benzyl alcohol;esters of aromatic acids such as ethyl benzoate and benzyl benzoate;esters of carbonic acid such as propylene carbonate and dimethylcarbonate; amides such as N,N-diethyl-toluamide, N-dodecyl-2-pyrrolidone, N-octyl-2-pyrrolidone, N-methyl-2-caprolactam, andN-dodecyl-caprolactam; fatty acids such as heptanoic acid and oleicacid; and oils such as sesame oil, peanut oil, and castor oil.

The organic solvent is typically added to the compositions in an amountranging from about 10 percent to about 70 percent by weight, from about15 percent to about 65 percent by weight, from about 20 percent to about60 percent by weight, from about 25 percent to about 55 percent byweight, from about 25 percent to about 50 percent by weight, from about25 percent to about 45 percent by weight, from about 25 percent to about40 percent by weight, or from about 25 percent to about 35 percent byweight, relative to the total weight of the composition. In otherembodiments, the amount of solvent in compositions of the invention canrange from any whole number percent to any other whole number percentwithin the range of from about 10 percent to about 70 percent by weight.The concentration of solvent allows for the level of liquid polymer inthe compositions to range from about 10 percent to about 90 percent byweight, from about 15 percent to about 85 percent by weight, from about20 percent to about 80 percent by weight, from about 25 percent to about75 percent by weight, from about 30 percent to about 70 percent byweight, from about 35 percent to about 65 percent by weight, from about40 percent to about 60 percent by weight, from about 45 percent to about55 percent by weight relative to the overall composition. In otherembodiments, the amount of liquid polymer in compositions of theinvention can range from any whole number percent to any other wholenumber percent within the range of from about 10 percent to about 90percent by weight. In one embodiment, the liquid polymer compositioncomprises between about 20 wt % and about 40 wt % biodegradable liquidpolyester, between about 40 wt % and about 60 wt % biocompatible organicsolvent, and optionally between about 10 wt % and about 30 wt % activepharmaceutical agent. The liquid polymer/solvent concentrations permitthe liquid polymer/solvent compositions to be easily injected withstandard syringes and small gauge needles (e.g., about 18-26 gauge). Thecompositions of the invention can be administered into the body of ahuman subject or other animal such as a dog, cat, horse, cow, goat,sheep, or pig.

The liquid polymer and organic solvent composition with an activepharmaceutical agent can be applied or injected into the body of asubject or onto an object (e.g., mesh, catheter, a screw, plate, tack,pin, staple, sponge, etc.) using a device such as a syringe or needle. Adevice with the composition thereon can be placed into the body of thesubject. Suitable routes of injection include, but are not limited to,any parenteral route, such as subcutaneous, intramuscular, andintradermal routes. Other routes of administration include, but are notlimited to, topical administration, or sublingual administration (suchas on a film or similar system). Following injection or use, the organicsolvent dissipates to leave a liquid bolus of polymer and activepharmaceutical agent. The liquid polymer component of the implantedpolymer/solvent compositions of the invention will flow and fill thevoids left by the organic solvent as it dissipates from the implantedmaterial. The implanted liquid polymer material remains as a liquid witha fluctuant (flowable) consistency so that it remains movable andcompressible and gradually biodegrades in the subject's body over time.Because the liquid polymer is not soluble in body fluid or water, thebolus within the body tissue does not dissipate by dissolution in bodyfluid, but remains as a cohesive mass.

The liquid polymer/solvent compositions can be used as controlledrelease compositions to provide a delivery system in which a drug orother biologically active agent is added to the liquid polymer/solventcomposition to form a liquid polymer pharmaceutical composition prior toinjection or other route of administration to the body. Upon exposure tobody fluid, the organic solvent dissolves or dissipates in the aqueoustissue fluid to leave the more viscous liquid polymer for release of theencapsulated or entrapped active agent. The liquid polymer implantformed from compositions of the present invention by the dissolution ordissipation of the solvent can be used to control the release ofbiologically active agents with low initial burst and extended releaseof the drug.

Liquid polymer pharmaceutical compositions of the invention have beenfound to release drugs in a patient over a surprisingly long period oftime, release a surprisingly high total amount of drug and allow formodulation of initial burst profiles to achieve a high or low initialburst, as desired. In various embodiments, an active pharmaceuticalagent in a liquid polymer pharmaceutical composition of the invention isreleased in a patient, for example as determined by measuring bloodserum levels of the agent in a patient, for greater than three days,greater than one week, greater than two weeks, greater than three weeks,greater than four weeks, greater than one month, greater than twomonths, greater than three months, greater than four months, greaterthan five months, greater than six months, greater than nine months, orgreater than one year. Such levels of agent can be at levels having apharmacologic or therapeutic effect.

An embodiment of the present invention is a method to treat, provide atherapy for, cure, or prevent a disease, disorder, or other ailment byadministration of a liquid polymer pharmaceutical composition comprisingan active pharmaceutical agent, as described in detail elsewhere herein.These methods can be used to treat, provide a therapy for, cure, orprevent microbial infections or any other infections by a pathogen,autoimmune disorders, allergies, inflammations, cancers, endocrinedisorders, metabolic disorders, neurological disorders, psychologicaldisorders, cardiovascular disorders, or any other diseases, disorders,or other ailments treated by the active pharmaceutical agents describedherein.

Active pharmaceutical agents (e.g., drugs) that are suitable for thepresent application are biologically active agents that provide abiological effect and that act locally or systemically in the treatment,therapy, cure and/or prevention of a disease, disorder, or otherailment. Examples of drugs include, without limitation, antimicrobials,anti-infectives, anti-parasitic drugs such as avermectins, antigens,anti-allergenics, steroidal anti-inflammatory agents, non-steroidalanti-inflammatory agents, anti-tumor agents, anticancer drugs,decongestants, miotics, anti-cholinergics, sympathomimetics, sedatives,hypnotics, psychic energizers, tranquilizers, endocrine/metabolicagents, hormones, GLP-1 agonists, androgenic steroids, estrogens,progestational agents, LHRH agonists and antagonists, somatotropins,narcotic antagonists, humoral agents, prostaglandins, analgesics,antispasmodics, antimalarials, antihistamines, cardioactive agents,antiparkinsonian agents, antihypertensive agents, vaccines, anti-virals,antipsychotics, immunosuppressants, anesthetics, antifungals,antiproliferatives, anticoagulants, antipyretics, antispasmodics, growthfactors, cell adhesion factors, cytokines, biological responsemodifiers, and nutritional agents.

The drug may be, for example, a small molecule organic compound or apolymer, such as a peptide, polypeptide, protein, DNA, or RNA material.The small molecule drug may be a hydrophobic drug, such ascorticosteroids such as prednisone, prednisolone, beclomethasone,fluticasone, methylprednisone, triamcinolone, clobetasol, halobetasol,and dexamethasone; azole medications such as metronidazole, fluconazole,ketoconazole, itraconazole, miconazole, dimetridazole, secnidazole,ornidazole, tinidazole, carnidazole, and panidazole; sex steroids suchas testosterone, estrogens such as estradiol, and progestins, includingesters thereof; statin drugs such as atorvastatin, simvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, and rosuvastatin;and antiandrogen drugs such as abiraterone, galeterone, orteronel, andenzalutamide and salts, esters, complexes, prodrugs and analogs of theforegoing.

Examples of peptide and polymeric drugs that are suitable for thepresent application include degarelix, abaloparatide, leuprolide(leuprorelin), exenatide, liraglutide, albiglutide, dulaglutide, basalinsulin, octreotide, goserelin, triptorelin, nafarelin, buserelin,histrelin, deslorelin, ganirelix, abarelix, cetrorelix, teverelix,lanreotide, carfilzomib, human growth hormone, interferon-alpha,interferon-beta, interferon-gamma, interleukin, calcitonin, growthhormone releasing peptides, glucagon-like peptides, granulocyte-colonystimulating factor, nerve growth factor, platelet-derived growth factor,insulin-like growth factor, vascular endothelial growth factor,fibroblast growth factor, bone morphogenic protein, erythropoietin,poly-L-lactic acid (PLLA), and salts, complexes, prodrugs, and analogsthereof.

Examples of specific additional drugs that may be utilized includehydrophilic and hydrophobic small molecule drugs such as rivastigminetartrate, cisplatin, carboplatin, paclitaxel, rapamycin, tacrolimus(fujimycin), bortezomib, trametinib, methotrexate, riociguat,macitentan, sumatriptan, anastozole, fulvestrant, exemestane,misoprostol, follicle-stimulating hormone, axitinib, paricalcitol,pomalidomide, dustasteride, doxycycline, doxorubicin, ciprofloxacin,quinolone, ivermectin, eprinomectin, doramectin, leflunomide,teriflunomide, haloperidol, diazepam, risperidone, olanzapine,amisulpride, aripiprazole, asenapine, clopazine, iloperidone,lurasidone, paliperidone, quetiapine, ziprasidone, bupivacaine,lidocaine, ropivacaine, naltrexone, fentanyl, buprenorphine,butorphanol, loperamide, afamelanotide (melanotan I), melanotan II,fingolimod, and salts, complexes, prodrugs, and analogs thereof.

One suitable drug that may be utilized in the present invention istestosterone or an ester thereof, including but not limited totestosterone undecanoate, also known as testosterone undecylate.Testosterone undecanoate is an ester of the hormone testosterone used inandrogen replacement therapy, primarily for the treatment of malehypogonadism. Testosterone undecanoate may also be used as a malecontraceptive. As previously known and described in the art,testosterone undecanoate may be administered to males over 18 years ofage as an initial 750 mg, 3 mL intramuscular dose, followed by another750 mg, 3 mL intramuscular dose after four weeks and further 750 mg, 3mL intramuscular doses every ten weeks thereafter. Further embodimentsof the invention include liquid polymer pharmaceutical compositions oftestosterone or testosterone undecanoate and use thereof in thetreatment of androgen deficiency, in particular male hypogonadism, byadministration to a subject having androgen deficiency, such as a malehaving hypogonadism in amounts and dosing schedules described above andby routes of administration as disclosed elsewhere herein.

Another suitable drug that may be utilized in the present invention isthe hormone degarelix or an ester thereof, such as degarelix acetate.Degarelix and esters thereof may be used in hormonal treatment ofprostate cancer. As previously known and described in the art, degarelixmay be administered to patients with hormone-dependent advanced prostatecarcinoma as an initial set of two 120 mg (i.e., totaling 240 mg)subcutaneous doses, followed by an 80 mg subcutaneous dose every 28 daysthereafter. Further embodiments of the invention include liquid polymerpharmaceutical compositions of degarelix or esters thereof and usethereof in the treatment of cancer (including prostate and breastcancer), endometriosis, uterine fibroids, or central precocious puberty(CPP), by administration to a patient in need thereof in amounts anddosing schedules described above and by routes of administration asdisclosed elsewhere herein. For example, liquid polymer compositionscontaining degarelix can be used to treat prostate cancer byadministration to a male having hormone-dependent advanced prostatecarcinoma.

Another suitable drug that may be utilized in the present invention isabaloparatide. Abaloparatide is a parathyroid hormone-related protein(PTHrP) analog drug that has attracted interest as a potential treatmentfor osteoporosis. Like the related drug teriparatide, but unlikebisphosphonates, abaloparatide is an anabolic (i.e., bone-growing)agent. As previously known and described in the art, transdermal andsubcutaneously injectable formulations of abaloparatide are currently inclinical development. Further embodiments of the invention includeliquid polymer pharmaceutical compositions of abaloparatide and usethereof in the treatment of osteoporosis by administration to a patienthaving osteoporosis in amounts and dosing schedules and by routes ofadministration as disclosed elsewhere herein.

Another suitable drug that may be utilized in the present invention isleuprolide acetate, a salt of the gonadotropin-releasing hormone analog(also known as a luteinizing hormone-releasing hormone (LHRH) agonist)leuprolide (also known as leuprorelin). Leuprolide acetate has founduses in the treatment of various forms of cancer, particularly prostateand breast cancers, as well as endometriosis, uterine fibroids, and(CPP). As previously known and described in the art, treatment ofadvanced prostate cancer with leuprolide acetate may consist of 7.5 mgintramuscular doses administered monthly, 22.5 mg intramuscular dosesadministered every three months, 30 mg intramuscular doses administeredevery four months, or 45 mg intramuscular doses administered every sixmonths. As previously known and described in the art, treatment ofendometriosis with leuprolide acetate may consist of 3.75 mgintramuscular doses administered monthly for up to six months, or two11.25 mg doses administered at three-month intervals. As previouslyknown and described in the art, treatment of uterine fibroids withleuprolide acetate may consist of 3.75 mg intramuscular dosesadministered monthly for up to three months, or a single 11.25 mgintramuscular dose. Further embodiments of the invention include liquidpolymer pharmaceutical compositions of leuprolide or esters thereof anduse thereof in the treatment of cancer (including prostate and breastcancer), endometriosis, uterine fibroids, or CPP by administration to apatient in need thereof in amounts and dosing schedules described aboveand by routes of administration as disclosed elsewhere herein.

The concentration of active pharmaceutical agent in compositions of theinvention depends on the drug that is included in the composition andmay range from 0.1% to 60% by weight of the composition or higher.Typically, the concentration of agent in the composition is between 10%and 50% by weight of the composition, such as between 20% and 40% byweight of the composition. In other embodiments, the amount of activepharmaceutical agent in compositions of the invention can range from anywhole number percent to any other whole number percent within the rangeof from about 1 percent to about 60 percent by weight.

Because a beneficial characteristic of the compositions disclosed hereinis improved extended release of an active pharmaceutical agent, theamount of active pharmaceutical agent will be suitable for long termtreatment with the agent in accordance with the time frames disclosedherein. Other embodiments of the invention include single dosageformulations of the liquid polymer pharmaceutical composition whichinclude the liquid polymer composition as described herein with anamount of an active pharmaceutical agent suitable for extended release.For example, such single dosage formulations can include sufficientactive pharmaceutical agent for treatment of a patient for greater thanthree days, greater than one week, greater than two weeks, greater thanthree weeks, greater than four weeks, greater than one month, greaterthan two months, greater than three months, greater than four months,greater than five months, greater than six months, greater than ninemonths, or greater than one year. Compositions may be administeredrepeatedly as needed (e.g. every month, every three months, every sixmonths, etc.).

The active pharmaceutical agent may be in the form of a liquid or afinely divided solid that is either dissolved or dispersed in the liquidpolymer/solvent composition. The agent is incorporated into thecomposition in an amount sufficient to achieve the desired therapeuticeffect, the desired release profile, and the desired period of release.There is no critical upper limit on the amount of the agent that isdispersed or dissolved in the liquid polymer/solvent solution as long asthe solution has a fluid viscosity acceptable for injection through astandard or small gauge syringe needle (e.g., gauge of 18-26). The lowerlimit of the amount of the agent incorporated into the liquidpolymer/solvent solution is dependent upon the activity of the agent,the release rate needed to achieve the desired therapeutic level, andthe length of time for treatment. Both soluble and insoluble activepharmaceutical agents may be incorporated into the liquidpolymer/solvent system.

Liquid polymer/solvent compositions comprising an active pharmaceuticalagent according to the present invention may appropriately be either a“solution” or a “suspension” of the active pharmaceutical agent in thesolvent. Particularly, it is to be understood that although liquidpolymer is dissolved in the solvent, the active pharmaceutical agent mayeither be dissolved in the solvent (as in a solution), or form solidparticles sufficiently large for suspension and sedimentation as part ofa heterogeneous mixture (as in a suspension).

The compositions may include various adjuvants or additives, such ascolorants, diluents, carriers, excipients, and stabilizers.

A further embodiment of the invention is a delivery system foradministration of a liquid polymer pharmaceutical composition to ananimal that includes a syringe component, a formulation component and anactive pharmaceutical agent. The formulation component includes abiodegradable liquid polyester comprising at least one carboxylic acidend group, with a ratio of monomer units to carboxylic acid end groupsbetween about 5:1 and about 90:1 and a biocompatible organic solvent. Inthis embodiment, the formulation component and the active pharmaceuticalagent are contained within the syringe component. The syringe componentcan be a single syringe containing the formulation component and activepharmaceutical agent, including without limitation, a mixing syringe ordual-chambered syringe configured to mix compositions contained withineach chamber (e.g., a formulation component and an active pharmaceuticalagent) prior to administration to a subject. Alternatively, the syringecomponent can be a two syringe system wherein a first syringe of the twosyringe system contains the formulation component and a second syringeof the two syringe system contains the active pharmaceutical agent. Inthis embodiment, prior to administration, the first and second syringescooperate to allow mixture of the formulation component and the activepharmaceutical agent which can then be administered to a patient byinjection.

Other embodiments of the invention include liquid polymer pharmaceuticalcompositions as described herein, including for example, wherein theactive pharmaceutical agent is selected from the group of testosterone,degarelix, abaloparatide, leuprolide and pharmaceutically acceptablesalts and esters thereof, for use in the treatment of conditionsdisclosed herein as being treatable by the active pharmaceutical agentin the composition.

Liquid polymer pharmaceutical compositions suitable for use in thepresent invention may be terminally sterilized for administration to ananimal, and in particular for administration to a human. Terminalsterilization may be accomplished, by way of non-limiting example, byelectron beam sterilization, or by other methods known to those skilledin the art.

The inventors have discovered that the rate of release of a drug from acomposition containing a liquid polymer delivery system that includes abiodegradable liquid polymer that has a carboxylic acid end group incombination with a biocompatible organic solvent provides markedlyimproved extended release of drugs following administration of thedelivery system into the body of an animal. As described below in theExamples, the duration of release is markedly extended beyond that whichis obtained when utilizing a similar liquid polymer delivery system thatdiffers in the identity of the initiator end group of the biodegradableliquid polymer.

The invention is illustrated by the following non-limiting examples.

Example 1: Prior Art Test Compositions

A 50/50 DL-Lactide/Caprolactone liquid polymer was made as disclosed inExample 1 of U.S. Pat. No. 8,187,640. The polymer was made usingdodecanol as an initiator. This polymer was combined with the solventN-methyl-2-pyrrolidone (NMP) (see, e.g., Example 3, 4 or 5 of the '640patent), in equal concentrations to provide a drug-free composition thatwas used as a control in the subsequent study.

Five different test compositions were made substantially as describedabove and using testosterone as the test drug. The first four testcompositions (Test Compositions 1 to 4, respectively) varied from eachother in the ratios of liquid polymer, solvent, and drug. TestComposition 1 contained 40% testosterone, 35% of the liquid polymer, and25% of the NMP solvent. Composition 2 contained 20% testosterone, 40% ofthe liquid polymer, and 40% of the NMP solvent. Composition 3 contained40% testosterone, 35% of the liquid polymer, and 25% of the NMP solvent.Composition 4 contained 20% testosterone, 40% of the liquid polymer, and40% of the NMP solvent. Test Composition 5 differed in the compositionof the liquid polymer. Whereas the control composition and the testcompositions 1 to 4 utilized a liquid polymer that was 50% DL-lactideand 50% ε-caprolactone, Test Composition 5 contained a liquid polymerthat was 75% DL-lactide and 25% ε-caprolactone, initiated withdodecanol. Test Composition 5 contained 40% Testosterone, 40% of theliquid polymer, and 20% of the NMP solvent.

Example 2: Release Profiles from Prior Art Compositions

Castrated male rats were divided into 6 groups, which were tested withthe control composition and Test Compositions 1 to 5, as described inExample 1. More specifically, each rat received a subcutaneous injectionof 100 mg/kg testosterone equivalent of the appropriate composition;control animals received approximately 10 mg of appropriate composition.Serum levels of testosterone were measured at intervals over a period of70 days. Results are shown in FIG. 1 .

As shown in FIG. 1 , no serum level of testosterone was detectable inrats that received the control composition containing polymer andsolvent but lacking testosterone (FIG. 1 (♦)). Testosterone levels foreach of the 5 test compositions were similar throughout the study (FIG.1 : Test Composition 1 (▪), Test Composition 2 (▴), Test Composition 3(x), Test Composition 4 (-), and Test Composition 5 (●)). Each of thetest groups showed an initial burst release spike in testosterone levelshortly after injection, and after 14 days, the quantity of drugreleased declined rapidly until day 21, with essentially no testosteronebeing detected by day 30.

Example 3: Compositions of the Invention Containing Testosterone

75/25 DL-lactide/caprolactone liquid polymers (75% DL-lactide and 25%ε-caprolactone) were made using methods substantially similar to thosedisclosed in Example 1 of U.S. Pat. No. 8,187,640 except that, in placeof dodecanol, glycolic acid was used as a polymer initiator, whichresults in polymers having carboxylic acid end groups that were notdisclosed in the '640 patent. These polymers were combined with asolvent (NMP) in equal concentrations to provide a drug-freepolymer/solvent composition.

Briefly, to produce liquid polymers of the invention described in thisExample 3, and/or as described in the subsequent Examples below, havinga target weight average molecular weight of 8 kDa, 15 kDa, 22 kDa, or 25kDa, the following process was used.

A 500 mL 2-part glass reactor equipped with a nitrogen inlet, anoverhead stirrer with a vacuum-capable stir guide and a vacuum outletleading to a vacuum trap and vacuum pump was assembled and placed in anoil bath. The oil bath was set at 100° C. and the reactor was placedunder vacuum to remove any residual moisture.

To produce a liquid polymer with a target weight average molecularweight of 8 kDa, 316.46 gm (2.20 mol) of DL-lactide, 83.54 gm (0.73 mol)of ε-caprolactone and 11.6 gm (0.1525 mol) of glycolic acid were weighedout. To produce a liquid polymer with a target average molecular weightof 15 kDa, 395.6 gm (2.7 mol) of DL-lactide, 52.2 gm (0.91 mol) ofε-caprolactone and 5.1 gm (0.07 mol) of glycolic acid were weighed out.To produce a liquid polymer with an average molecular weight of 15 kDa,316.8 g (2.2 mol) of DL-lactide, 83.4 g (0.73 mol) of ε-caprolactone and5.8 g (0.08 mol) of glycolic acid were weighed out. To produce a liquidpolymer with an average molecular weight of 25 kDa, 395.3 g (2.7 mol) ofDL-lactide, 104.5 g (0.91 mol) of ε-caprolactone, and 4.0 g (0.05 mol)of glycolic acid were weighed out. It is noted that the quantities ofpolymer and initiator shown in this Example are illustrative and thatthe exact quantities of polymer and initiator may vary slightly whendifferent lots of polymer are used. The calculations used to achieve adesired or target average molecular weight are within the ability of oneskilled in the art.

For each polymer composition, the vacuum on the reactor was broken withnitrogen and the reactor charged with DL-lactide, glycolic acid andε-caprolactone via a glass funnel. The stirrer was turned to 10-50 rpm,the oil bath set to 160° C., and the system vacuum purged and backflushed with nitrogen three times. The reactor was then left under aslight nitrogen purge.

A catalyst solution was prepared by weighing ca. 0.3 gm of tin(II)2-ethylhexanaote (stannous octoate) into a 10 mL volumetric flask anddiluting to the mark with anhydrous toluene. For the 8 kDa polymer, theamount needed to add 0.03 wt % stannous octoate based on monomer weightwas calculated as 0.12 g (4 mL) to inject. For the 15 kDa and 22 kDapolymers, the amount needed to add 0.03 wt % stannous octoate based onmonomer weight was calculated as 0.15 g (5 mL) to inject. The catalystcalculations used to achieve a desired or target average molecularweight are within the ability of one skilled in the art.

For all polymer compositions described in this and subsequent Examples,once the monomers had melted and the oil bath reached 160° C., thecatalyst was injected via a syringe equipped with a 6-inch blunt tipped20 g needle with stirring. The polymerization reaction was continued for16-18 hours. After the appropriate reaction time the vacuum trap wasimmersed in an ice bath and the nitrogen inlet closed. Vacuum wasapplied slowly to the stirred reaction mix for 4-6 hours with anultimate vacuum of −22 to −25 in. Hg. Unreacted monomer was collected inthe vacuum trap. After the appropriate time the vacuum was discontinued,the reactor purged with nitrogen, removed from the oil bath and theliquid polymer poured into a glass or PYREX® (low-thermal-expansionplastic borosilicate glass) container and cooled. Yield wasapproximately 85% for all polymer compositions.

Weight average molecular weight of the polymers was determined by gaspermeation chromatography (GPC) with a refractive index detector (e.g.,Agilent 1260 Infinity Quaternary LC with Agilent G1362A Refractive IndexDetector).

To produce various formulations of the invention using polymer, solventand drug, the following procedure was generally used. Polymer producedas discussed above was weighed into a polypropylene jar andN-methyl-2-pyrrolidone (NMP) (or in Composition C below, the indicatedmixture of NMP and benzyl benzoate) was added to the liquid polymer. Themixture was heated in an oven to assist in the dissolution and/ordispersion of the NMP in the polymer. Complete homogenous dissolutionrequired mixing with SPEEDMIXER™ (i.e., a high-speed mixer; FlackTek,Landrum, S.C.) or a roller mill. The resulting solution was a viscous,but more flowable liquid polymer which was at that point a drug-freepolymer/solvent composition. The active pharmaceutical ingredient (drug)(e.g., testosterone, testosterone cypionate, testosterone undecanoate,referring to this Example 3 and also Examples 5, 7 and 13 below) wasadded to the polymer solution and mixed until homogenously dispersed.

Three different test compositions of the invention were made using thisnew liquid polymer as described above and using testosterone as the testdrug. Test Composition A contained a liquid polymer having a molecularweight of 8 kDa and had a composition of 30% liquid polymer, 30% NMPsolvent, and 40% Testosterone. Test Composition B contained a liquidpolymer having a molecular weight of 22 kDa and had a composition of 30%liquid polymer, 30% NMP solvent, and 40% Testosterone. Test CompositionC contained a liquid polymer having a molecular weight of 15 kDa and hada composition of 30% liquid polymer, 40% testosterone, and 30% solventthat was a 30/70 mixture of NMP and benzyl benzoate.

Example 4: Release Profiles from Compositions of the InventionContaining Testosterone

Castrated male rats were divided into 3 groups, which were tested withTest Compositions A to C described in Example 3. Each rat received asubcutaneous injection of 100 mg/kg testosterone equivalent of theappropriate composition. Serum levels of testosterone were measured atintervals of approximately 7 days over a period of at least 80 days.Briefly, blood samples were collected and processed for measurement ofserum testosterone concentrations by liquid chromatography/massspectroscopy (LC/MS) at pre-dose, 30 minutes, 1, 3 and 10 hours and days1, 3, 7, 10, 14, 17, 21, 24, 28, 31, 35, 42, 49, 56, 63, 70, 77, 84, 92,108, and 120 post-dose, or at days otherwise indicated in subsequentExamples. Results of this experiment are shown in FIG. 2 .

As shown in FIG. 2 , each of the 3 test groups showed an initial burstrelease spike in testosterone level shortly after injection, followed bylevels of testosterone between approximately 5 ng and approximately 20ng until at least day 60 (Test Composition A (▪), Test Composition B(♦), Test Composition C (▴)).

Therapeutic levels of testosterone of at least 3 ng/ml were maintained60 days in all test compositions of the present invention, in contrastto the 21 days obtained with similar compositions of the prior art. Thisresult was surprising because the test formulations of the inventionutilized a carboxylic acid (i.e., glycolic acid) as a polymer initiator,which initiator is significantly more hydrophilic than the dodecanolinitiator disclosed in the '640 patent. Because it would be expectedthat a faster release rate would be obtained with a more hydrophilicpolymer, as disclosed in '640, one skilled in the art would not expectthat use of the carboxylic acid initiated polymer system of the presentapplication would provide for a greatly extended duration of release.

However, the tests shown in Examples 1 to 4 establish that a liquidpolymer delivery system containing a carboxylic acid initiated polymersurprisingly provides an unexpectedly long duration of release of adrug, such as a hydrophobic drug like a steroid drug such astestosterone. Additional tests in which a hydrophobic drug such astestosterone is replaced by its more hydrophobic ester were conducted inorder to attempt to minimize or eliminate the initial burst release seenin the above examples.

Example 5: Compositions of the Invention Containing a Testosterone Ester

75/25 DL-Lactide/Caprolactone liquid polymers (75% DL-lactide and 25%ε-caprolactone) were made using the methods as described in Example 3above utilizing glycolic acid as a polymer initiator. This polymer wascombined, as described in Example 3, with a solvent to provide adrug-free polymer/solvent delivery system.

Three different test compositions of the invention were madesubstantially as described above and using testosterone cypionate as thetest drug. Test Composition D contained a liquid polymer having amolecular weight of 22 kDa and had a composition of 30% liquid polymer,50% NMP solvent, and 20% testosterone cypionate. Test Composition Econtained a liquid polymer having a molecular weight of 25 kDa and had acomposition of 30% liquid polymer, 45% NMP solvent, and 25% testosteronecypionate. Test Composition F contained a liquid polymer having amolecular weight of 25 kDa and had a composition of 30% liquid polymer,50 NMP solvent, and 20% testosterone cypionate.

Example 6: Release Profiles from Testosterone Cypionate Compositions ofthe Invention

Castrated male rats were divided into 3 groups, which were tested withTest Compositions D (FIG. 3 , (▪)), E (FIG. 3 , (♦)) or F (FIG. 3 , (▴))as described in Example 5. Each rat received a subcutaneous injection of70 mg/kg testosterone equivalent of the appropriate composition. Serumlevels of testosterone were measured as described in Example 4 atintervals of approximately 7 days over a period of at least 80 days.Results are shown in FIG. 3 .

As shown in FIG. 3 , none of the 3 groups injected with the liquidpolymer/solvent/testosterone ester composition showed an initial burstrelease spike in testosterone level after injection. Rather, in allthree cases, testosterone levels rose quickly for the first several daysfollowing injection, reaching a peak at approximately day 18, and thendecreasing until approximately day 60.

Example 7: Compositions of the Invention Containing a Testosterone Ester

75/25 DL-Lactide/Caprolactone liquid polymers (75% DL-lactide and 25%ε-caprolactone) were made as described in Example 3 above utilizingglycolic acid as a polymer initiator. This polymer was combined, asdescribed in Example 3, with a solvent to provide a drug-freepolymer/solvent.

Four different test compositions of the invention were madesubstantially as described above and using testosterone undecanoate asthe test drug. Test Composition G contained a liquid polymer having amolecular weight of 8 kDa and had a composition of 20% liquid polymer,60% NMP solvent, and 20% testosterone undecanoate. Test Composition Hcontained a liquid polymer having a molecular weight of 8 kDa and had acomposition of 30% liquid polymer, 50% NMP solvent, and 20% testosteroneundecanoate. Test Composition I contained a liquid polymer having amolecular weight of 22 kDa and had a composition of 20% liquid polymer,60% NMP solvent, and 20% testosterone undecanoate. Test Composition Jcontained a liquid polymer having a molecular weight of 22 kDa and had acomposition of 30% liquid polymer, 50% NMP solvent, and 20% testosteroneundecanoate.

Example 8: Release Profiles from Testosterone Undecanoate Compositionsof the Invention

Castrated male rats were divided into 4 groups, which were tested withone of Test Compositions G, H, I or J described in Example 7. Each ratreceived a subcutaneous injection of 70 mg testosterone equivalent ofthe appropriate composition. Serum levels of testosterone were measuredas described in Example 4 at intervals of approximately 7 days over aperiod of at least 80 days. Results are shown in FIG. 4 .

As shown in FIG. 4 , none of the 4 groups injected with the liquidpolymer/solvent/testosterone ester composition showed an initial burstrelease spike in testosterone level after injection (Test Composition G(▪), Test Composition H (▴), Test Composition I (▴), and TestComposition J (●)). Rather, in all cases, testosterone levels rosequickly for the first several days following injection, reaching a peakat approximately day 18, and then decreasing until approximately day 80.

The tests shown in Examples 5 to 8 establish that a liquid polymerdelivery system containing a carboxylic acid initiated polymersurprisingly provides an unexpectedly long duration of release of anester of a hydrophobic drug, such as a steroid drug like testosterone.The combination of the liquid polymer delivery system with the polymerhaving carboxylic acid end groups and the ester form of a hydrophobicdrug provided a similar long duration of release of drug, but without aburst release of drug from the delivery system.

Example 9: Comparison of Invention to Prior Art Utilizing a Peptide Drug

A test was performed to compare release of peptide drug from the priorart liquid polymer composition of Example 1 and the liquid polymercomposition of the invention of Example 3. Specifically, a leuprolideacetate solution and a liquid polymer solution containing 75% DL-lactideand 25% ε-caprolactone produced using the methods described in Example 1(liquid polymer containing 75% DL-lactide and 25% ε-caprolactoneinitiated with dodecanol, e.g., as in Test Composition 5 of Example 1,except that the drug is a peptide, leuprolide acetate, in this Example9) or Example 3 (liquid polymer containing 75% DL-lactide and 25%ε-caprolactone initiated with glycolic acid, e.g., as in TestComposition A of Example 3, except that the drug is the peptide,leuprolide acetate, in this Example 9) were mixed and weighed into avial to form compositions containing 30% liquid polymer, 58% w/w NMP and12% w/w leuprolide acetate.

Room temperature phosphate buffered saline (PBS) was added to the vials.The vials were placed in an orbital incubator shaker at 37° C. and 125rpm. 1 mL of PBS was removed for analysis at selected time points andreplaced with fresh buffer. An in vitro release study was performed inPBS pH 7.4 and the percentage of leuprolide acetate released from theliquid polymer compositions was measured by high performance liquidchromatography (HPLC). Results are shown in FIG. 5 , where the drugrelease over time from the prior art liquid polymer initiated withdodecanol (▴) is compared to the drug release over time from the liquidpolymer of the invention initiated with glycolic acid (▪).

As shown in FIG. 5 , release of peptide drug occurred from the prior artcomposition in an immediate spike during the first day followingadministration, and essentially no more drug was released following thisinitial spike.

In contrast, no spike release occurred from the composition of thepresent invention. Rather, a steady release of peptide drug was obtainedover a period of 63 days (1512 hours), following which drug releaseslowed.

Example 10: Preparation of 14 kDa Liquid Polymer Solutions in NMPContaining Leuprolide Acetate

75/25 DL-lactide/caprolactone liquid polymers (75% DL-lactide and 25%ε-caprolactone) were made as described in Example 3 above utilizingglycolic acid as a polymer initiator. This polymer was combined, asdescribed in Example 3, with a solvent to provide a drug-freepolymer/solvent composition. The polymer/solvent compositions were thencombined with a peptide drug, leuprolide acetate (LA) solution to formthe compositions used in this example.

More specifically, using the methods as generally described in Example3, 75% DL-lactide and 25% ε-caprolactone liquid polymer compositionswere prepared and combined with NMP solvent. Also as described inExample 3, weight average molecular weight of the polymers wasdetermined by gas permeation chromatography (GPC) with a refractiveindex detector (e.g., Agilent 1260 Infinity Quaternary LC with AgilentG1362A Refractive Index Detector). In this example, liquid polymershaving a weight average molecular weight of 14 kDa were produced.

Leuprolide acetate (LA) (4.5 grams) was dissolved in 5.5 grams of NMP(45/55 w/w leuprolide acetate solution in NMP). Complete dissolutionrequired mixing with speed mixer or roller mill at room temperature. Thetwo compositions (polymer/solvent and drug/solvent) are then mixed justprior to use (e.g., injection or in vitro release assay), for example,by using a dual chambered single syringe or two different syringes, andthen weighed into a vial. For in vitro release studies, as described inExample 9 and in Example 11 below, room temperature PBS was added to thevial. The vial was placed in an orbital incubator shaker at 37° C. and125 rpm. 1 mL of PBS was removed for analysis at selected time pointsand replaced with fresh buffer.

Three compositions containing: leuprolide acetate, a liquid polymerhaving a molecular weight of 14 kDa and a solvent (NMP) were made. Eachcomposition contained leuprolide acetate at a concentration of 12% w/w.Composition K contained polymer at a concentration of 30% and NMP at aconcentration of 58%. Composition L contained polymer at a concentrationof 35% and NMP at a concentration of 53%. Composition M containedpolymer at a concentration of 40% and NMP at a concentration of 48%. Thecompositions were made by combining an amount of the liquid polymerobtained in Example 3 (liquid polymer containing 75% DL-lactide and 25%ε-caprolactone initiated with glycolic acid) with the appropriate amountof solvent as indicated above, and then combining with leuprolideacetate.

Example 11: Release Profiles from 14 kDa Liquid Polymer Compositionswith Leuprolide

An in vitro release study as described in Example 9 (i.e., determined byHPLC in phosphate buffered saline (PBS) pH 7.4) was performed. In thisstudy, the compositions K, L and M of Example 10 were tested for invitro release of leuprolide acetate. Results are shown in FIG. 6 . Asshown in FIG. 6 , release of peptide drug was similar from all testedcompositions. Release was observed to be faster from compositions thatcontained a lower concentration of liquid polymer and higherconcentration of solvent. Release was fastest from Composition K (♦)(polymer at a concentration of 30% and NMP at a concentration of 58%)and slowest from Composition M (▴) (polymer at a concentration of 40%and NMP at a concentration of 48%), and continued steadily during the1600 hours (66 days) of the study. The pattern of release from each ofCompositions K (♦), L (▪), and M (▴) was similar.

Example 12: 8 kDa Liquid Polymer Solutions in NMP Containing LeuprolideAcetate

75/25 DL-lactide/caprolactone liquid polymers (75% DL-lactide and 25%ε-caprolactone) were made as described in Example 3 above utilizingglycolic acid as a polymer initiator. This polymer was combined, asdescribed in Example 3, with a solvent to provide a drug-freepolymer/solvent composition. The polymer/solvent compositions were thencombined with a peptide drug, leuprolide acetate (LA) solution, asdescribed in Example 10 to form the compositions used in this example.In this example, the liquid polymers had a weight average molecularweight of 8 kDa.

Three compositions containing leuprolide acetate, a liquid polymerhaving a molecular weight of 8 kDa, and a solvent (NMP) were made. Eachcomposition contained leuprolide acetate at a concentration of 12% w/w.Composition N contained polymer at a concentration of 30% and NMP at aconcentration of 58%. Composition 0 contained polymer at a concentrationof 35% and NMP at a concentration of 53%. Composition P containedpolymer at a concentration of 40% and NMP at a concentration of 48%. Thecompositions were made by combining an amount of the liquid polymerobtained in Example 3 (liquid polymer containing 75% DL-lactide and 25%ε-caprolactone initiated with glycolic acid) with the appropriate amountof solvent as indicated above, and then combining with leuprolideacetate as generally described in Example 10.

Example 13: Release Profiles from 8 kDa Liquid Polymer Compositions withLeuprolide

An in vitro release study as described in Example 9 was performed. Inthis study, the compositions of N, O and P from Example 12 were testedfor in vitro release of leuprolide acetate. Results are shown in FIG. 7.

As shown in FIG. 7 , release of peptide drug was similar from all testedcompositions. Release was observed to be slightly faster fromcompositions that contained a lower concentration of liquid polymer andhigher concentration of solvent. Release from all compositions wassteady during the 1600 hours (66 days) of the study. The pattern ofrelease from each of Compositions N (▪), O (▴), and P (●) was similar.Additionally, release from the compositions of Example 12 was somewhatmore rapid than from the compositions of Example 10 (see FIG. 6 ).However, this difference does not appear to be significant.

Example 14: 22 kDa Liquid Polymer Solutions in NMP ContainingTestosterone

This example evaluated the use of alternative liquid polymercompositions and alternative carboxylic acid initiators as a furtherdemonstration of the formulations and methods of the present invention.Specifically, a 75/25 DL-lactide/caprolactone liquid polymer (75%DL-lactide and 25% ε-caprolactone) was made as described in Example 3above, except that lactic acid was used as the polymer initiator. Inaddition, a 75/25 DL-lactide/trimethylene carbonate (TMC) liquid polymer(75% DL-lactide/25% trimethylene carbonate (TMC) polymer) was alsoproduced using the methods as generally described in Example 3, usingglycolic acid as the polymer initiator. Each of these polymers wascombined, as described in Example 3, with a solvent (NMP) to provide adrug-free polymer/solvent composition, and then each of thesepolymer/solvent compositions was further combined with testosteroneundecanoate using the methods generally described in Example 3.

Two test compositions containing testosterone undecanoate, a liquidpolymer having a molecular weight of 22 kDa, and a solvent (NMP) weremade. Each composition contained testosterone undecanoate at aconcentration of 20 wt %. Composition Q contained a 75% DL-lactide/25%ε-caprolactone polymer initiated with lactic acid at a concentration of30 wt % and NMP at a concentration of 50 wt %. Composition R contained a75% DL-lactide/25% trimethylene carbonate (TMC) polymer initiated withglycolic acid at a concentration of 30 wt % and NMP at a concentrationof 50 wt %. A control formulation contained a 75% DL-lactide/25%ε-caprolactone polymer initiated with glycolic acid at a concentrationof 30 wt % and NMP at a concentration of 50 wt % (corresponding toComposition J from Example 7).

Example 15: Release Profiles from 22 kDa Liquid Polymer Compositionswith Testosterone

Castrated male Sprague Dawley rats were divided into 2 groups, whichwere tested, respectively, with Test Compositions Q and R described inExample 14. Each rat received a subcutaneous injection of theappropriate composition to deliver a target dose of 34 mg oftestosterone undecanoate. Serum levels of testosterone were measured atintervals of approximately 7 days over greater than 120 days. Briefly,blood samples were collected and processed for measurement of serumtestosterone concentrations by liquid chromatography/mass spectroscopy(LC/MS/MS) at pre-dose, and at intervals beyond 120 days post-dose.Results are shown in FIGS. 8A and 8B (Control Composition (equivalent toComposition J from Example 7) (▴); Test Composition Q (▪); TestComposition R (♦)). FIG. 8A shows testosterone release (ng/mL) asnon-normalized data from this experiment, and FIG. 8B shows testosteronerelease (ng/mL per mg/kg) as data normalized for both the amount offormulation received by individual animals and for individual animalbody weight.

As shown in FIGS. 8A and 8B, the release of testosterone from the TestCompositions Q and R was similar in magnitude and pattern to the ControlComposition. In all cases, testosterone levels rose quickly for thefirst several days following injection, reaching a peak at approximatelyday 18, and then decreasing gradually over an extended time. TestCompositions Q and R were continuing to release testosterone past the126-day time point. This example again demonstrates that a liquidpolymer delivery system containing a liquid polymer with carboxylic acidend groups of the invention surprisingly provides an unexpectedly longduration of release of a drug in vivo, such as testosterone undecanoate.In addition, this example shows that the liquid polymer composition ofthe invention is not limited to polymers formed from DL-lactide andε-caprolactone, and that the carboxylic acid end group is not limited toend groups formed by a glycolic acid initiator (i.e., that a variety ofliquid polymers and a variety of initiators that add carboxylic acid endgroups are useful according to the invention).

Various modifications of the above described invention will be evidentto those skilled in the art. It is intended that such modifications areincluded within the scope of the following claims.

The invention claimed is:
 1. An extended release pharmaceutical composition for administration into the body of an animal or human, comprising: a biodegradable liquid polyester having a carboxylic acid end group; a biocompatible organic solvent or combination of solvents; and an active pharmaceutical agent, wherein: the extended release pharmaceutical composition is formulated to release the active pharmaceutical agent for a period of one month or greater; the extended release pharmaceutical composition is free of a polyester without a carboxylic acid end group; and the biodegradable liquid polyester comprises lactide residues and monomer residues selected from the group consisting of caprolactone, trimethylene carbonate, and combinations thereof.
 2. The extended release pharmaceutical composition of claim 1, wherein the carboxylic acid end group is formed from an initiator that is selected from the group consisting of GABA (gamma-amino butyric acid), GHB (gamma-hydroxybutyric acid), lactic acid, glycolic acid, citric acid, and undecylenic acid.
 3. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester comprises at least about 50% lactide residues.
 4. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester comprises about 75% lactide residues.
 5. The extended release pharmaceutical composition of claim 1, wherein the monomer residues selected from the group consisting of caprolactone, trimethylene carbonate, and combinations thereof are in an amount less than about 50%.
 6. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester comprises about 25% monomer residues selected from the group consisting of caprolactone, trimethylene carbonate, and combinations thereof.
 7. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester is selected from the group consisting of 75:25 lactide:caprolactone and 75:25 lactide:trimethylene carbonate.
 8. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester has a weight-average molecular weight between about 5 kDa and about 40 kDa.
 9. The extended release pharmaceutical composition of claim 1, wherein the biocompatible organic solvent or combination of solvents is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone, N-cycylohexyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide, acetic acid, lactic acid, ethanol, propanol, methyl lactate, ethyl lactate, methyl acetate, diethylene glycol monomethyl ether, glycofurol, glycerol formal, isopropylidene glycerol, dimethyl sulfoxide, ε- caprolactone, butyrolactone, propylene glycol, polyethylene glycol, glycerol, 1,3-butyleneglycol, methoxypolyethylene glycol, methoxypropylene glycol, acetone, methyl ethyl ketone, tetrahydrofuran and combinations thereof.
 10. The extended release pharmaceutical composition of claim 1, wherein the composition comprises between about 20 wt % and about 40 wt % of the biodegradable liquid polyester and between about 40 wt % and about 60 wt % of the biocompatible organic solvent or combination of solvents.
 11. The extended release pharmaceutical composition of claim 1, wherein the active pharmaceutical agent is selected from a hydrophobic small molecule drug and a polymeric drug.
 12. A method of forming a biodegradable, non-solid implant in situ in a body, comprising injecting the extended release pharmaceutical composition of claim 1 into the body.
 13. A method of delivering an active pharmaceutical agent to a body, comprising injecting the extended release pharmaceutical composition of claim 1 into the body.
 14. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester has a weight-average molecular weight between about 10 kDa and about 40 kDa.
 15. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester has a weight-average molecular weight between about 15 kDa and about 40 kDa.
 16. The extended release pharmaceutical composition of claim 1, wherein the extended release pharmaceutical composition is formulated to release the active pharmaceutical agent for a period of three months or greater.
 17. The extended release pharmaceutical composition of claim 1, wherein a duration of release of the active pharmaceutical agent from the composition is longer than a duration of release obtained from a composition comprising a biodegradable liquid polyester without a carboxylic acid end group.
 18. The extended release pharmaceutical composition of claim 1, wherein the biodegradable liquid polyester comprises at least about 50% lactide residues and monomer residues selected from the group consisting of caprolactone, trimethylene carbonate, and combinations thereof.
 19. A liquid polymer pharmaceutical composition for administration into the body of an animal or human, comprising: a biodegradable liquid polyester having a carboxylic acid end group and at least about 50% lactide residues and monomer residues selected from the group consisting of caprolactone, trimethylene carbonate, and combinations thereof; a biocompatible organic solvent or combination of solvents; and an active pharmaceutical agent, wherein: the liquid polymer pharmaceutical composition is formulated to release the active pharmaceutical agent for a period of one month or greater; and the biodegradable liquid polyester is the only polyester in the liquid polymer pharmaceutical composition.
 20. The liquid polymer pharmaceutical composition of claim 19, wherein the biodegradable liquid polyester has a weight-average molecular weight between about 5 kDa and about 40 kDa.
 21. The liquid polymer pharmaceutical composition of claim 19, wherein the composition comprises between about 20 wt % and about 40 wt % of the biodegradable liquid polyester and between about 40 wt % and about 60 wt % of the biocompatible organic solvent or combination of solvents.
 22. The liquid polymer pharmaceutical composition of claim 19, wherein a duration of release of the active pharmaceutical agent from the composition is longer than a duration of release obtained from a composition comprising a biodegradable liquid polyester without a carboxylic acid end group. 